WO1998032850A1 - Dispositif d'interface informatique pour ecran a plasma de type ca - Google Patents

Dispositif d'interface informatique pour ecran a plasma de type ca Download PDF

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Publication number
WO1998032850A1
WO1998032850A1 PCT/US1998/000468 US9800468W WO9832850A1 WO 1998032850 A1 WO1998032850 A1 WO 1998032850A1 US 9800468 W US9800468 W US 9800468W WO 9832850 A1 WO9832850 A1 WO 9832850A1
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nucleic acid
acid molecule
seq
sequence
cis element
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PCT/US1998/000468
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English (en)
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WO1998032850A9 (fr
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Thai D. Nguyen
Jon R. Polansky
Pu Chen
Hua Chen
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The Regents Of The University Of California
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Priority to EP98901761A priority Critical patent/EP1012271B1/fr
Priority to JP53201798A priority patent/JP2001509669A/ja
Priority to CA002278782A priority patent/CA2278782C/fr
Priority to AU58204/98A priority patent/AU742405B2/en
Priority to NZ336860A priority patent/NZ336860A/en
Priority to DE69838553T priority patent/DE69838553T2/de
Publication of WO1998032850A1 publication Critical patent/WO1998032850A1/fr
Publication of WO1998032850A9 publication Critical patent/WO1998032850A9/fr
Priority to NO993653A priority patent/NO993653L/no

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/156—Polymorphic or mutational markers

Definitions

  • the present invention is in the fields of diagnostics, prognosis, and treatment, and concerns methods and reagents for diagnosing and treating glaucoma and related disorders.
  • Glaucomas are a group of debilitating eye diseases that are the leading cause of preventable blindness in the United States and other developed countries.
  • Primary Open Angle Glaucoma (“POAG”) is the most common form of glaucoma. The disease is characterized by the alteration of the trabecular meshwork, leading to obstruction of the normal ability of aqueous humor to leave the eye without closure of the space (e.g., the "angle") between the iris and cornea (see, Vaughan, D. et al, In: General Ophthalmology, Appleton & Lange, Norwalk, CT, pp. 213-230 (1992)).
  • a characteristic of such obstruction in this disease is an increased intraocular pressure (“IOP”), resulting in progressive visual loss and blindness if not treated appropriately and in a timely fashion.
  • IOP intraocular pressure
  • the disease is estimated to affect between 0.4% and 3.3% of all adults over 40 years old (Leske, M.C. et al., Amer. J. Epidemiol. 113:1843-1846 (1986); Bengtsson, B., Br. ⁇ . Ophthamol. 73:483-487 (1989); Strong, N.P., Ophthal. Physiol. Opt. 12:3-7 (1992)). Moreover, the prevalence of the disease rises with age to over 6% of those 75 years or older (Strong, N.P., Ophthal. Physiol. Opt. 12:3-7 (1992)). A link between the IOP response of patients to glucocorticoids and the disease of POAG has long been suspected.
  • Patent Application No: 08/649,432 filed May 17, 1996, the entire disclosure of which is hereby incorporated by reference as if set forth at length herein, disclosed a novel protein sequence highly induced by glucocorticoids in the endothelial lining cells of the human trabecular meshwork.
  • Nguyen et al, U.S. Patent Application No: 08/649,432 also disclosed the cDNA sequence for that protein, the protein itself, molecules that bind to it, and nucleic acid molecules that encode it, and provided improved methods and reagents for diagnosing glaucoma and related disorders, as well as for diagnosing other diseases or conditions, such as cardiovascular, immunological, or other diseases or conditions that affect the expression or activity of the protein.
  • the present invention provides improved diagnostic agents, prognostic agents, therapeutic agents and methods.
  • An object of the invention is to provide a method for diagnosing glaucoma in a patient which comprises the steps: (A) incubating under conditions permitting nucleic acid hybridization: a marker nucleic acid molecule, said marker nucleic acid molecule comprising a nucleotide sequence of a polynucleotide that specifically hybridizes to a polynucleotide that is linked to a TIGR promoter, and a complementary nucleic acid molecule obtained from a cell or a bodily fluid of said patient, wherein nucleic acid hybridization between said marker nucleic acid molecule, and said complementary nucleic acid molecule obtained from said patient permits the detection of a polymorphism whose presence is predictive of a mutation affecting TIGR response in said patient; (B) permitting hybridization between said marker nucleic acid molecule and said complementary nucleic acid molecule obtained from said patient; and (C) detecting the presence of said polymorphism, wherein the detection of the polymorphism is diagnostic of glau
  • Another object of the invention is to provide a method for prognosing glaucoma in a patient which comprises the steps: (A) incubating under conditions permitting nucleic acid hybridization: a marker nucleic acid molecule, said marker nucleic acid molecule comprising a nucleotide sequence of a polynucleotide that specifically hybridizes to a polynucleotide that is linked to a TIGR promoter, and a complementary nucleic acid molecule obtained from a cell or a bodily fluid of said patient, wherein nucleic acid hybridization between said marker nucleic acid molecule, and said complementary nucleic acid molecule obtained from said patient permits the detection of a polymorphism whose presence is predictive of a mutation affecting TIGR response in said patient; (B) permitting hybridization between said marker nucleic acid molecule and said complementary nucleic acid molecule obtained from said patient; and (C) detecting the presence of said polymorphism, wherein the detection of the polymorphism is prognos
  • Another object of the invention is to provide marker nucleic acid molecules capable of specifically detecting TIGRmtl, TIGRmtl, TIGRmt3, TIGRmt , TIGRmt ⁇ and TIGRsvl .
  • Another object of the invention is to provide a method for diagnosing steroid sensitivity in a patient which comprises the steps: (A) incubating under conditions permitting nucleic acid hybridization: a marker nucleic acid molecule, the marker nucleic acid molecule comprising a nucleotide sequence of a polynucleotide that is linked to a TIGR promoter, and a complementary nucleic acid molecule obtained from a cell or a bodily fluid of the patient, wherein nucleic acid hybridization between the marker nucleic acid molecule, and the complementary nucleic acid molecule obtained from the patient permits the detection of a polymorphism whose presence is predictive of a mutation affecting TIGR response in the patient; (B) permitting hybridization between said TIGR-
  • nucleic acid molecule that comprises the sequence of SEQ ID NO: 1, recombinant DNA molecules containing a polynucleotide that specifically hybridizes to SEQ ID NO: 1 and substantially purified molecules that specifically bind to a nucleic acid molecule that comprises the sequence of SEQ ID NO: 1.
  • nucleic acid molecule that comprises the sequence of SEQ ID NO: 3, recombinant DNA molecules containing a polynucleotide that specifically hybridizes to SEQ ID NO: 3 and substantially purified molecules that specifically bind to a nucleic acid molecule that comprises the sequence of SEQ ID NO: 3.
  • Additional objects of the invention provide a nucleic acid molecule that comprises the sequence of SEQ ID NO: 4, recombinant DNA molecules containing a polynucleotide that specifically hybridizes to SEQ ID NO: 4 and substantially purified molecules that specifically bind to a nucleic acid molecule that comprises the sequence of SEQ ID NO: 4.
  • Additional objects of the invention provide a nucleic acid molecule that comprises the sequence of SEQ ID NO: 5, recombinant DNA molecules containing a polynucleotide that specifically hybridizes to SEQ ID NO: 5 and substantially purified molecules that specifically bind to a nucleic acid molecule that comprises the sequence of SEQ ID NO: 5.
  • An additional object of the present invention is to provide a method of treating glaucoma which comprises administering to a glaucomatous patient an effective amount of an agent that inhibits the synthesis of a TIGR protein.
  • the molecules of the present invention may be used to diagnose diseases or conditions which are characterized by alterations in the expression of extracellular proteins.
  • Figures 1A, IB, IC, ID and IE provide the nucleic acid sequence of a TIGR promoter region (SEQ ID NO: 1) from an individual without glaucoma.
  • Figures 2A, 2B, 2C and 2D provide the location and sequence changes highlighted in bold associated with glaucoma mutants TIGRmtl, TIGRmtl, TIGRmt3, TIGRmtl, TIGRmt ⁇ , and TIGRsvl (SEQ ID NO: 2).
  • Figures 3A, 3B, 3C, 3D, 3E, 3F, and 3G provide nucleic acid sequences of a
  • TIGR promoter and TIGR exons, TIGR introns and TIGR downstream sequences (SEQ ID NO: 3, SEQ ID NO: 4, and SEQ ID NO: 5).
  • Figure 4 provides a diagrammatic representation of the location of primers on the TIGR gene promoter for Single Strand Conformational Polymorphism (SSCP) analysis.
  • SSCP Single Strand Conformational Polymorphism
  • Figure 5 provides a diagrammatic representation of the TIGR exons and the arrangement of SSCP primers.
  • Figure 6 provides a homology analysis of TIGR homology with olf actomedin and olfactomedin-related proteins.
  • Figure 7 shows the nucleotide sequence of ⁇ GR (SEQ ID NO: 26).
  • Figure 8 shows the amino acid sequence of ⁇ GR (SEQ ID NO: 32).
  • glaucoma has its art recognized meaning, and includes both primary glaucomas, secondary glaucomas, juvenile glaucomas, congenital glaucomas, and familial glaucomas, including, without limitation, pigmentary glaucoma, high tension glaucoma and low tension glaucoma and their related diseases.
  • the methods of the present invention are particularly relevant to the diagnosis of POAG, OAG, juvenile glaucoma, and inherited glaucomas.
  • the methods of the present invention are also particularly relevant to the prognosis of POAG, OAG, juvenile glaucoma, and inherited glaucomas.
  • a disease or condition is said to be related to glaucoma if it possesses or exhibits a symptom of glaucoma, for example, an increased intra-ocular pressure resulting from aqueous outflow resistance (see, Vaughan, D. et al, In: General Ophthamology, Appleton & Lange, Norwalk, CT, pp. 213-230 (1992)).
  • a symptom of glaucoma for example, an increased intra-ocular pressure resulting from aqueous outflow resistance (see, Vaughan, D. et al, In: General Ophthamology, Appleton & Lange, Norwalk, CT, pp. 213-230 (1992)).
  • the preferred agents of the present invention are discussed in detail below.
  • the agents of the present invention are capable of being used to diagnose the presence or severity of glaucoma and its related diseases in a patient suffering from glaucoma (a "glaucomatous patient").
  • the agents of the present invention are also capable of being used to prognose the presence or severity of glaucoma and its related diseases in a person not yet suffering from any clinical manifestations of glaucoma.
  • Such agents may be either naturally occurring or non-naturally occurring.
  • a naturally occurring molecule may be "substantially purified,” if desired, such that one or more molecules that is or may be present in a naturally occurring preparation containing that molecule will have been removed or will be present at a lower concentration than that at which it would normally be found.
  • the agents of the present invention will preferably be "biologically active" with respect to either a structural attribute, such as the capacity of a nucleic acid to hybridize to another nucleic acid molecule, or the ability of a protein to be bound by antibody (or to compete with another molecule for such binding).
  • a structural attribute such as the capacity of a nucleic acid to hybridize to another nucleic acid molecule, or the ability of a protein to be bound by antibody (or to compete with another molecule for such binding).
  • such an attribute may be catalytic, and thus involve the capacity of the agent to mediate a chemical reaction or response.
  • ⁇ GR protein refers to a protein having the amino acid sequence of SEQ ID NO: 32.
  • agents of the present invention comprise nucleic acid molecules, proteins, and organic molecules.
  • HTM cells Human trabecular meshwork (HTM) cells are endothelial like cells which line the outflow channels by which aqueous humor exits the eye; altered synthetic function of the cells may be involved in the pathogenesis of steroid glaucoma and other types of glaucoma. Sustained steroid treatment of these cells are interesting because it showed that a major difference was observed when compared to 1-2 day glucocorticoid (GC) exposure. This difference appears relevant to the clinical onset of steroid glaucoma (1-6 weeks).
  • GC glucocorticoid
  • the clone Based on studies of 35s methionine cell labeling, the clone has the characteristics recently discovered for the major GC-induced extracellular glycoprotein in these cells, which is a sialenated, N- glycosylated molecule with a putative inositol phosphate anchor.
  • the induction of mRNA approached 4% of the total cellular mRNA.
  • the mRNA increased progressively over 10 days of dexamethasone treatment.
  • the ⁇ .2 clone is 2.0 Kb whereas the Northern blotting shows a band of 2.5 Kb.
  • the 3' end of the clone contains two consensus polyadenylation signals.
  • PjTIGR clone A genomic clone was isolated and designated PjTIGR clone (ATCC No: 97570, American Type Culture Collection, Rockville, Maryland). In-situ hybridization using the PjTIGR clone shows a TIGR gene and/or a sequence or sequences that specifically hybridize to the ⁇ GR gene located at chromosome 1, q21-27, and more preferably to the ⁇ GR gene located at chromosome 1, q22-26, and most preferably to the ⁇ GR gene located at chromosome 1, q24.
  • Clone PjTIGR comprises human genomic sequences that specifically hybridize to the ⁇ GR gene cloned into the B ⁇ mHI site of vector pCYPAC (Ioannou et al, Nature Genetics, 6:84-89 (1994) herein incorporated by reference).
  • ⁇ GR gene refers to the region of DNA involved in producing a ⁇ GR protein; it includes, without limitation, regions preceeding and following the coding region as well as intervening sequences between individual coding regions.
  • ⁇ GR exon refers to any interrupted region of the TIGR gene that serves as a template for a mature ⁇ GR mRNA molecule.
  • ⁇ GR intron refers to a region of the TIGR gene which is non- coding and serves as a template for a ⁇ GR mRNA molecule.
  • TIGR gene near the D1S2536 marker with a LOD score of 6.0 (Richard et al, American Journal of Human Genetics 51.5: 915-921 (1993), herein incorporated by reference); Frazer et al, Genomics 14.3: 574-578 (1992), herein incorporated by reference; Research Genetics, Huntsville, Alabama).
  • Other markers in this region include: D1S210; D1S1552; D1S2536; D1S2790; SHGC-12820; and D1S2558.
  • Sequences located upstream of the TIGR coding region are isolated and sequenced in a non-glaucomic individual.
  • the upstream sequence is set forth in SEQ ID. No. 1. Sequence comparisons of the upstream region of a non-glaucoma individual and individuals with glaucoma identify a number of mutations in individuals with glaucoma. These mutations are illustrated in Figure 2. Five mutations are identified.
  • TIGRmtl is the result of a replacement of a cytosine with a guanine at position 4337 (SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3).
  • TIGRmtl is the result of a replacement of a cytosine with a thymine at position 4950 (SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3).
  • TIGRmt3 is the result of an addition in the following order of a guanine, a thymine, a guanine, and a thymine (GTGT) at position 4998 (SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3).
  • GTGT thymine
  • TIGRmti is the result of a replacement of an adenine with a guanine at position 4256 (SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3).
  • TIGRmt ⁇ is the result of a replacement of a guanine with an adenine at position 4262 (SEQ ID NO: 1, SEQ ID NO: 2 and SEQ ID NO: 3).
  • One or more of TIGRmtl, TIGRmtl, TIGRmt3, TIGRmt4, and TIGRmt ⁇ can be homozygous or heterozygous.
  • Sequence comparisons of the upstream region of a non-glaucoma individual and individuals with glaucoma identify at least one sequence variation in individuals with glaucoma.
  • One such sequence variant is illustrated in Figure 2.
  • TIGRsvl is the result of a replacement of an adenine with a guanine at position 4406 (SEQ ID NO: 1, SEQ ID NO: 2 and SEQ ID NO: 3).
  • Molecules comprising sequences upstream of the TIGR coding region provide useful markers for polymorphic studies.
  • Such molecules include primers suitable for single strand conformational polymorphic studies, examples of which are as follows: forward primer “Sk-la”: 5'-TGA GGC TTC CTC TGG AAA C-3' (SEQ ID NO: 6); reverse primer “ca2”: 5'-TGA AAT CAG CAC ACC AGT AG-3' (SEQ ID NO: 7); forward primer “CA2”: 5'-GCA CCC ATA CCC CAA TAA TAG-3' (SEQ ID NO: 8); reverse primer “Pr+1”: 5'-AGA GTT CCC CAG ATT TCA CC-3' (SEQ ID NO: 9); forward primer "Pr-1”: 5'-ATC TGG GGA ACT CTT CTC AG-3' (SEQ ID NO: 10); reverse primer "Pr+2(4A2)”: 5'-TAC AGT TGT TGC AGA TAC G
  • molecules comprising sequences within ⁇ GR exons provide useful markers for polymorphic studies.
  • Such ' molecules include primers suitable for single strand conformational polymorphic studies, examples of which are as follows: forward primer “KSIX”: 5'-CCT GAG ATG CCA GCT GTC C-3' (SEQ ID NO: 17); reverse primer “SK1XX”: 5'-CTG AAG CAT TAG AAG CCA AC-3' (SEQ ID NO: 18); forward primer “KS2al”: 5'-ACC TTG GAC CAG GCT GCC AG-3' (SEQ ID NO: 19); reverse primer “SK3” 5'-AGG TTT GTT CGA GTT CCA G-3' (SEQ ID NO: 20); forward primer “KS4": 5'-ACA ATT ACT GGC AAG TAT GG-3' (SEQ ID NO: 21); reverse primer "SK6A”: 5'-CCT TCT CAG CCT TGC TAC C-3' (SEQ ID NO: 22); forward primer "KS
  • Pr+3(4A), Pr-3(4A), Pr-3(4A), Pr+2(4A1), and Pr+1(4A) are diagramatically set forth in Figure 4.
  • the location of primers: KSIX, SK1XX, Ks2al, SK3, KS4, SK6A, KS5, SK8, and KS6 are diagramatically set forth in Figure 5.
  • the primary structure of the TIGR coding region initiates from an ATG initiation site (SEQ ID NO:3, residues 5337-5339) and includes a 20 amino acid consensus signal sequence a second ATG (SEQ ID NO: 3, residues 5379-5381), indicating that the protein is a secretory protein.
  • the nucleotide sequence for the TIGR coding region is depicted in Figure 7 (SEQ ID NO: 26).
  • the protein contains an N-linked glycosylation site located in the most hydrophilic region of the molecule.
  • the amino terminal portion of the protein is highly polarized and adopts alpha helical structure as shown by its hydropathy profile and the Garnier-Robison structure analysis.
  • the protein contains a 25 amino acid hydrophobic region near its carboxy terminus.
  • This region may comprise a glucocorticoid- induced protein (GIP) anchoring sequence.
  • GIP glucocorticoid- induced protein
  • TIGR 12-0-tetradecanolyphorbol-13-acetate
  • cis elements DNA motifs or cis elements are shown in Figure 1. These motifs include, without limitation, glucocorticoid response motif(s), shear stress response motif(s), NFKB recognition motif(s), and API motif(s). The locations of these and other motifs are diagramatically set forth in Figure 1.
  • cis elements capable of binding refers to the ability of one or more of the described cis elements to specifically bind an agent. Such binding may be by any chemical, physical or biological interaction between the cis element and the agent, including, but not limited, to any covalent, steric, agostic, electronic and ionic interaction between the cis element and the agent.
  • specifically binds refers to the ability of the agent to bind to a specified cis element but not to wholly unrelated nucleic acid sequences.
  • a preferred class of agents comprises ⁇ GR nucleic acid molecules (" ⁇ GR molecules”). Such molecules may be either DNA or RNA.
  • ⁇ GR molecules comprises the ⁇ GR protein, its peptide fragments, fusion proteins, and analogs.
  • rat PRL gene is highly restricted to pituitary lactotroph cells and is induced by the cAMP-dependent protein kinase A pathway.
  • At least one of the redundant pituitary specific elements (PRL-FP111) of the proximal rat PRL promotor is required for this protein kinase A effect (Rajnarayan et al, Molecular Endochronology 4: 502-512 (1995), herein incorporated by reference).
  • a sequence corresponding to an upstream motif or cis element characteristic of PRL-FP111 is set forth in Figure 1 at residues 370-388 and 4491-4502, respectively.
  • transcription of ⁇ GR molecules can be effected by agents capable of altering the biochemical properties or concentration of molecules that bind the PRL-FP111 upstream motif or cis element.
  • agents capable of altering the biochemical properties or concentration of molecules that bind the PRL-FP111 upstream motif or cis element can be used in the study of glaucoma pathogenesis.
  • agents can also be used in the study of glaucoma prognosis.
  • such agents can be used in the treatment of glaucoma.
  • GR/PR consensus sequence recognized by both the glucocorticoid receptor of rat liver and the progesterone receptor from rabbit uterus, has been reported to be involved in glucocorticoid and progesterone-dependent gene expression (Von der Ahe et al, Nature 313: 706-709 (1985), herein incorporated by reference).
  • a sequence corresponding to a GC/PR upstream motif or cis element is set forth in Figure 1 at residues 433-445.
  • transcription of ⁇ GR molecules can be effected by agents capable of altering the biochemical properties or concentration of glucocorticoid or progesterone or their homologues, including, but not limited to, the concentration of glucocorticoid or progesterone or their homologues bound to an GC/PR upstream motif or cis element.
  • agents capable of altering the biochemical properties or concentration of glucocorticoid or progesterone or their homologues including, but not limited to, the concentration of glucocorticoid or progesterone or their homologues bound to an GC/PR upstream motif or cis element.
  • agents can be used in the study of glaucoma pathogenesis.
  • such agents can also be used in the study of glaucoma prognosis.
  • such agents can be used in the treatment of glaucoma.
  • Shear stress motif (SSRE) or cis element has been identified in a number of genes including platelet-derived growth factor B chain, tissue plasminogen activator (tPA), ICAM-1 and TGF- ⁇ l (Resnick et al, Proc. Natl Acad. Sci. (USA) 80: 4591-4595 (1993), herein incorporated by reference). Transcription of these genes has been associated with humoral stimuli such as cytokines and bacterial products as well as hemodynamic stress forces. Sequences corresponding to a upstream shear stress motif or cis element are set forth in Figure 1 at residues 446-451, 1288-1293, 3597- 3602, 4771-4776, and 5240-5245, respectively.
  • transcription of ⁇ GR molecules can be effected by agents capable of altering the biochemical properties or concentration of molecules capable of binding the shear stress motif.
  • agents capable of altering the biochemical properties or concentration of molecules capable of binding the shear stress motif can be used in the study of glaucoma pathogenesis.
  • agents can also be used in the study of glaucoma prognosis.
  • agents can be used in the treatment of glaucoma.
  • GRE glucocorticoid response upstream motif
  • cis element A consensus sequence for a glucocorticoid response upstream motif (GRE) or cis element has been characterized (Beato, Cell 56: 335-344 (1989); Becker et al, Nature 314: 686-688 (1986), herein incorporated by reference; Sakai et al, Genes and Development 1: 1144-1154 (1988), herein incorporated by reference). Genes containing this upstream motif or cis element are regulated by glucocorticoids, progesterone, androgens and mineral corticoids (Beato, Cell 56: 335-344 (1989)).
  • transcription of ⁇ GR molecules can be effected by agents capable of altering the biochemical properties or concentration of molecules capable of binding a glucocorticoid response upstream motif or cis element.
  • agents capable of altering the biochemical properties or concentration of molecules capable of binding a glucocorticoid response upstream motif or cis element can be used in the study of glaucoma pathogenesis.
  • agents can also be used in the study of glaucoma prognosis.
  • such agents can be used in the treatment of glaucoma.
  • transcription of ⁇ GR molecules can be effected by agents capable of altering the biochemical properties or concentration of p53 or its homologues, including, but not limited to, the concentration of p53 or its homologues bound to an CBE upstream motif or cis element.
  • agents capable of altering the biochemical properties or concentration of p53 or its homologues including, but not limited to, the concentration of p53 or its homologues bound to an CBE upstream motif or cis element.
  • agents can be used in the study of glaucoma pathogenesis.
  • agents can also be used in the study of glaucoma prognosis.
  • such agents can be used in the treatment of glaucoma.
  • NFE Nuclear factor ets-like
  • transcription of ⁇ GR molecules can be effected by agents capable of altering the biochemical properties or concentration of nuclear factors or their homologues, including, but not limited to, the concentration of nuclear factors or their homologues bound to an NFE upstream motif or cis element.
  • agents capable of altering the biochemical properties or concentration of nuclear factors or their homologues including, but not limited to, the concentration of nuclear factors or their homologues bound to an NFE upstream motif or cis element.
  • agents can be used in the study of glaucoma pathogenesis.
  • such agents can also be used in the study of glaucoma prognosis.
  • such agents can be used in the treatment of glaucoma.
  • KTF.l-CS upstream motif or cis element
  • transcription of ⁇ GR molecules can be effected by agents capable of altering the biochemical properties or concentration of KTF.l-CS or its homologues, including, but not limited to, the concentration of KTF.l-CS or its homologues bound to a KTF.l-CS upstream motif or cis element
  • agents capable of altering the biochemical properties or concentration of KTF.l-CS or its homologues including, but not limited to, the concentration of KTF.l-CS or its homologues bound to a KTF.l-CS upstream motif or cis element
  • agents can be used in the study of glaucoma pathogenesis.
  • such agents can also be used in the study of glaucoma prognosis.
  • such agents can be used in the treatment of glaucoma.
  • a progesterone responsive element that maps to the far upstream steroid dependent DNase hypersensitive site of chicken lysozyme chromatin has been characterized (Hecht et al, EMBO J. 7: 2063-2073 (1988), herein incorporated by reference).
  • the element confers hormonal regulation to a heterologous promoter and is composed of a cluster of progesterone receptor binding sites.
  • a sequence corresponding to an upstream motif or cis element characteristic of PRE is set forth in Figure 1 at residues 987-1026.
  • transcription of ⁇ GR molecules can be effected by agents capable of altering the biochemical properties or concentration of molecules capable of binding a progesterone responsive PRE upstream motif or cis element.
  • Such agents may be useful in the study of glaucoma pathogenesis. In another embodiment, such agents can also be used in the study of glaucoma prognosis. In another embodiment such agents can be used in the treatment of glaucoma.
  • a sequence (ETF-EGFR) has been characterized which serves as a motif for a tr ⁇ ns-active transcription factor that regulates expression of the epidermal growth factor receptor (Regec et al, Blood 85:2711-2719 (1995), herein incorporated by reference).
  • a sequence corresponding to an ETF-EGFR upstream motif or cis element is set forth in Figure 1 at residues 1373-1388.
  • transcription of TIGR molecules can be effected by agents capable of altering the biochemical properties or concentration of nuclear factors or their homologues, including, but not limited to, the concentration of nuclear factors or their homologues bound to an ETF-EGFR upstream motif or cis element.
  • agents capable of altering the biochemical properties or concentration of nuclear factors or their homologues including, but not limited to, the concentration of nuclear factors or their homologues bound to an ETF-EGFR upstream motif or cis element.
  • agents can be used in the study of glaucoma pathogenesis.
  • such agents can also be used in the study of glaucoma prognosis.
  • such agents can be used in the treatment of glaucoma.
  • SRE-cFos trans-acting factor
  • a sequence corresponding to an SRE-cFos upstream motif or cis element is set forth in Figure 1 at residues 1447-1456.
  • transcription of ⁇ GR molecules can be effected by agents capable of altering the biochemical properties or concentration of nuclear factors or their homologues, including, but not limited to, the concentration of nuclear factors or their homologues bound to an SRE-cFos upstream motif or cis element.
  • Such agents can be used in the study of glaucoma pathogenesis. In another embodiment, such agents can also be used in the study of glaucoma prognosis. In another embodiment such agents can be used in the treatment of glaucoma.
  • Alu repetitive elements are unique to primates and are interspersed within the human genome with an average spacing of 4Kb. While some Alu sequences are actively transcribed by polymerase IH, normal transcripts may also contain Alu- derived sequences in 5' or 3' untranslated regions (Jurka and Mikahanljaia, /. Mol Evolution 32: 105-121 (1991), herein incorporated by reference, Claveria and Makalowski, Nature 371: 751-752 (1994), herein incorporated by reference).
  • transcription of ⁇ GR molecules can be effected by agents capable of altering the biochemical properties or concentration of nuclear factors or their homologues, including, but not limited to, the concentration of nuclear factors or their homologues bound to an Alu upstream motif or cis element.
  • agents capable of altering the biochemical properties or concentration of nuclear factors or their homologues including, but not limited to, the concentration of nuclear factors or their homologues bound to an Alu upstream motif or cis element.
  • agents can be used in the study of glaucoma pathogenesis.
  • such agents can also be used in the study of glaucoma prognosis.
  • such agents can be used in the treatment of glaucoma.
  • VBP vitellogenin gene-binding protein
  • transcription of TIGR molecules can be effected by agents capable of altering the biochemical properties or concentration of VBP or its homologues, including, but not limited to, the concentration of VBP or its homologues bound to an VBP upstream motif or cis element
  • agents capable of altering the biochemical properties or concentration of VBP or its homologues including, but not limited to, the concentration of VBP or its homologues bound to an VBP upstream motif or cis element
  • agents can be used in the study of glaucoma pathogenesis.
  • such agents can also be used in the study of glaucoma prognosis.
  • such agents can be used in the treatment of glaucoma.
  • a structural motif (Malt-CS) or cis element involved in the activation of all promoters of the maltose operons in Escherichia coli and Klebsiella pneumoniae has been characterized (Vidal-Ingigliardi et al, J. Mol. Biol 218: 323-334 (1991), herein incorporated by reference).
  • a sequence corresponding to a upstream Malt-CS motif or cis element is set forth in Figure 1 at residues 1832-1841.
  • transcription of TIGR molecules can be effected by agents capable of altering the biochemical properties or concentration of molecules capable of binding the upstream Malt-CS motif or cis element.
  • Such agents can be used in the study of glaucoma pathogenesis. In another embodiment, such agents can also be used in the study of glaucoma prognosis. In another embodiment such agents can be used in the treatment of glaucoma.
  • a consensus sequence for an estrogen receptor upstream motif or cis element has been characterized (ERE) (Forman et al, Mol. Endocrinology 4: 1293-1301 (1990), herein incorporated by reference; de Verneuil et al, Nucleic Acid Res. 18: 4489-4497 (1990), herein incorporated by reference; Gaub et al, Cell 63: 1267-1276 (1990), herein incorporated by reference.
  • transcription of TIGR molecules can be effected by agents capable of altering the biochemical properties or concentration, of the estrogen receptor or its homologues bound to an upstream motif or cis element.
  • agents capable of altering the biochemical properties or concentration, of the estrogen receptor or its homologues bound to an upstream motif or cis element can be used in the study of glaucoma pathogenesis.
  • agents can also be used in the study of glaucoma prognosis.
  • such agents can be used in the treatment of glaucoma.
  • transcription of TIGR molecules can be effected by agents capable of altering the biochemical properties or concentration of nuclear factors or their homologues, including, but not limited to, the concentration of nuclear factors or their homologues bound to an NF-mutagen upstream motif or cis element.
  • agents capable of altering the biochemical properties or concentration of nuclear factors or their homologues including, but not limited to, the concentration of nuclear factors or their homologues bound to an NF-mutagen upstream motif or cis element.
  • agents can be used in the study of glaucoma pathogenesis.
  • such agents can also be used in the study of glaucoma prognosis.
  • such agents can be used in the treatment of glaucoma.
  • myc-PRF c-myc upstream motif or cis element
  • Myc-PRF interacts with another widely distributed protein, myc-CFl (common factor 1), which binds nearby and this association may be important in myc-PRF repression.
  • myc-CFl common factor 1
  • a sequence corresponding to an upstream motif or cis element capable of binding myc-PRF is set forth in Figure 1 at residues 2403-2416.
  • transcription of ⁇ GR molecules can be effected by agents capable of altering the biochemical properties or concentration of myc-PRF or its homologues, including, but not limited to, the concentration of myc-PRF or its homologues bound to an myc-PRF upstream motif or cis element
  • agents capable of altering the biochemical properties or concentration of myc-PRF or its homologues including, but not limited to, the concentration of myc-PRF or its homologues bound to an myc-PRF upstream motif or cis element
  • agents can be used in the study of glaucoma pathogenesis.
  • such agents can also be used in the study of glaucoma prognosis.
  • such agents can be used in the treatment of glaucoma.
  • Human transcription factor activator protein 2 (AP2) is a transcription factor that has been shown to bind to Spl, nuclear factor 1 (NF1) and simian virus 40 transplantation (SV40 T) antigen binding sites. It is developmentally regulated (Williams and Tijan, Gene Dev. 5: 670-682 (1991), herein incorporated by reference; Mitchell et al, Genes Dev.
  • transcription of ⁇ GR molecules can be effected by agents capable of altering the biochemical properties or concentration of AP2 or its homologues, including, but not limited to, the concentration of AP2 or its homologues bound to an upstream motif or cis element.
  • agents capable of altering the biochemical properties or concentration of AP2 or its homologues, including, but not limited to, the concentration of AP2 or its homologues bound to an upstream motif or cis element.
  • agents may be useful in the study of glaucoma pathogenesis.
  • such agents can also be used in the study of glaucoma prognosis.
  • such agents can be used in the treatment of glaucoma.
  • Drosophila RNA polymerase ⁇ heat shock transcription factor is a transcription factor that has been shown to be required for active transcription of an hsp 70 gene (Parker and Topol, Cell 37: 273-283 (1984), herein incorporated by reference). Sequences corresponding to an upstream motif or cis element capable of binding HSTF are set forth in Figure 1 at residues 2622-2635, and 5105-5132.
  • transcription of ⁇ GR molecules can be effected by agents capable of altering the biochemical properties or concentration of HSTF or its homologues, including, but not limited to, the concentration of HSTF or its homologues bound to an HSTF upstream motif or cis element.
  • agents can be used in the study of glaucoma pathogenesis.
  • such agents can also be used in the study of glaucoma prognosis.
  • such agents can be used in the treatment of glaucoma.
  • transcription of ⁇ GR molecules can be effected by agents capable of altering the biochemical properties or concentration of molecules that bind the SBF upstream motif or cis element.
  • agents capable of altering the biochemical properties or concentration of molecules that bind the SBF upstream motif or cis element can be used in the study of glaucoma pathogenesis.
  • agents can also be used in the study of glaucoma prognosis.
  • agents can be used in the treatment of glaucoma.
  • NF1 motif or cis element has been identified which recognizes a family of at least six proteins (Courtois, et al, Nucleic Acid Res. 18: 57-64 (1990), herein incorporated by reference; Mul et al, J. Virol 64: 5510-5518 (1990), herein incorporated by reference; Rossi et al, Cell 52: 405-414 (1988), herein incorporated by reference; Gounari et al, EMBO ⁇ .
  • the NF1 protein will bind to an NF1 motif or cis element either as a dimer (if the motif is palindromic) or as an single molecule (if the motif is not palindromic).
  • the NF1 protein is induced by TGF ⁇ (Faisst and Meyer, Nucleic Acid Research 20: 3-26 (1992), herein incorporated by reference). Sequences corresponding to an upstream motif or cis element capable of binding NF1 are set forth in Figure 1 at residues 2923-2938, 4143-4167, and 4886-4900, respectively.
  • transcription of ⁇ GR molecules can be effected by agents capable of altering the biochemical properties or concentration of NF1 or its homologues, including, but not limited to, the concentration of NF1 or its homologues bound to an upstream motif or cis element.
  • agents capable of altering the biochemical properties or concentration of NF1 or its homologues including, but not limited to, the concentration of NF1 or its homologues bound to an upstream motif or cis element.
  • agents can be used in the study of glaucoma pathogenesis.
  • agents can also be used in the study of glaucoma prognosis.
  • such agents can be used in the treatment of glaucoma.
  • NF-MHCIIA/B conserveed regulatory sequences (NF-MHCIIA/B) of a rabbit major histocompatability complex (MHC) class II gene are responsible for binding two distinct nuclear factors NF-MHCIIA and NF-MHCIIB and are believed to be involved in the regulation of coordinate expression of the class ⁇ genes — eg. MHC class II gene in B lymphocytes (Sittisombut Molecular and Cellular Biology 5: 2034- 2041 (1988), herein incorporated by reference).
  • a sequence corresponding to an NF- MHCIIA/B upstream motif or cis element is set forth in Figure 1 at residues 2936- 2944.
  • transcription of TIGR molecules can be effected by agents capable of altering the biochemical properties or concentration of NF-MHCIIA or NF-MHCIIB or their homologues, including, but not limited to, the concentration of NF-MHCHA or NF-MHCIIB or their homologues bound to an NF-MHCIIA/B upstream motif or cis element.
  • agents capable of altering the biochemical properties or concentration of NF-MHCIIA or NF-MHCIIB or their homologues including, but not limited to, the concentration of NF-MHCHA or NF-MHCIIB or their homologues bound to an NF-MHCIIA/B upstream motif or cis element.
  • agents can be used in the study of glaucoma pathogenesis.
  • such agents can also be used in the study of glaucoma prognosis.
  • such agents can be used in the treatment of glaucoma.
  • PEA 1 binding motifs or cis elements have been identified (Piette and Yaniv, EMBO /. 5: 1331-1337 (1987), herein incorporated by reference).
  • the PEA1 protein is a transcription factor that is reported to bind to both the polyoma virus and c-/os enhancers
  • a sequence corresponding to an upstream motif or cis element capable of binding PEA1 is set forth in Figure 1 at residues 3285-3298.
  • transcription of ⁇ GR molecules can be effected by agents capable of altering the biochemical properties or concentration of PEA1 or its homologues, including, but not limited to, the concentration of PEA1 or its homologues bound to an upstream motif or cis element.
  • Such agents can be used in the study of glaucoma pathogenesis. In another embodiment, such agents can also be used in the study of glaucoma prognosis. In another embodiment such agents can be used in the treatment of glaucoma.
  • ICS cis-acting regulatory element
  • IFN interferon
  • transcription of ⁇ GR molecules can be effected by agents capable of altering the biochemical properties or concentration of nuclear factors or their homologues, including, but not limited to, the concentration of nuclear factors or their homologues bound to an ICS upstream motif or cis element.
  • agents capable of altering the biochemical properties or concentration of nuclear factors or their homologues including, but not limited to, the concentration of nuclear factors or their homologues bound to an ICS upstream motif or cis element.
  • agents can be used in the study of glaucoma pathogenesis.
  • such agents can also be used in the study of glaucoma prognosis.
  • such agents can be used in the treatment of glaucoma.
  • ISGF2 upstream motif or cis element
  • a consensus sequence for an ISGF2 upstream motif or cis element has been characterized (Iman et al, Nucleic Acids Res. 18: 6573-6580 (1990), herein incorporated by reference; Harada et al, Cell 63: 303-312 (1990), herein incorporated by reference; Yu-Lee et al, Mol Cell Biol 10: 3087-3094 (1990), herein incorporated by reference; Pine et al, Mol Cell Biol 10: 32448-2457 (1990), herein incorporated by reference).
  • ISGF2 is induced by interferon ⁇ and ⁇ , prolactin and virus infections.
  • a sequence corresponding to an upstream motif or cis element capable of binding ISGF2 is set forth in Figure 1 at residues 4170-4179.
  • transcription of ⁇ GR molecules can be effected by agents capable of altering the biochemical properties or concentration of ISGF2 or its homologues, including, but not limited to, the concentration of ISGF2 or its homologues bound to an upstream motif or cis element
  • agents capable of altering the biochemical properties or concentration of ISGF2 or its homologues including, but not limited to, the concentration of ISGF2 or its homologues bound to an upstream motif or cis element
  • agents can be used in the study of glaucoma pathogenesis.
  • such agents can also be used in the study of glaucoma prognosis.
  • such agents can be used in the treatment of glaucoma.
  • transcription of TIGR molecules can be effected by agents capable of altering the biochemical properties or concentration of zinc.
  • agents capable of altering the biochemical properties or concentration of zinc.
  • agents can be used in the study of glaucoma pathogenesis.
  • agents can also be used in the study of glaucoma prognosis.
  • agents can be used in the treatment of glaucoma.
  • transcription of ⁇ GR molecules can be effected by agents capable of altering the biochemical properties or concentration of molecules that bind the CAP/CRP-galO upstream motif or cis element.
  • agents capable of altering the biochemical properties or concentration of molecules that bind the CAP/CRP-galO upstream motif or cis element can be used in the study of glaucoma pathogenesis.
  • agents can also be used in the study of glaucoma prognosis.
  • such agents can be used in the treatment of glaucoma.
  • Human transcription factor activator protein 1 is a transcription factor that has been shown to regulate genes which are highly expressed in transformed cells such as stromelysin, c-/os, 04-anti-trypsin and collagenase (Gutman and Wasylyk, EMBO J. 9.7: 2241-2246 (1990), herein incorporated by reference; Martin et al, Proc. Natl Acad. Sci.
  • transcription of ⁇ GR molecules can be effected by agents capable of altering the biochemical properties or concentration of API or its homologues, including, but not limited to, the concentration of API or its homologues bound to an upstream motif or cis element.
  • agents capable of altering the biochemical properties or concentration of API or its homologues including, but not limited to, the concentration of API or its homologues bound to an upstream motif or cis element.
  • agents capable of altering the biochemical properties or concentration of API or its homologues including, but not limited to, the concentration of API or its homologues bound to an upstream motif or cis element.
  • agents can be used in the study of glaucoma pathogenesis.
  • agents can also be used in the study of glaucoma prognosis.
  • agents can be used in the treatment of glaucoma.
  • SRY is a DNA binding protein known to bind to a CACA-rich region in the sry gene (Vriz et al, Biochemistry and Molecular Biology International 37: 1137-1146 (1995), herein incorporated by reference).
  • a sequence corresponding to an upstream motif or cis element capable of binding SRY is set forth in Figure 1 at residues 4625-4634.
  • transcription of ⁇ GR molecules can be effected by agents capable of altering the biochemical properties or concentration of SRY or its homologues, including, but not limited to, the concentration of SRY or its homologues bound to an upstream motif or cis element.
  • agents capable of altering the biochemical properties or concentration of SRY or its homologues, including, but not limited to, the concentration of SRY or its homologues bound to an upstream motif or cis element.
  • agents may be useful in the study of glaucoma pathogenesis.
  • such agents can also be used in the study of glaucoma prognosis.
  • such agents can be used in the treatment of glaucoma.
  • transcription of ⁇ GR molecules can be effected by agents capable of altering the biochemical properties or concentration of GC2-GH or its homologues, including, but not limited to, the concentration of GC2-GH or its homologues bound to an upstream motif or cis element.
  • agents capable of altering the biochemical properties or concentration of GC2-GH or its homologues including, but not limited to, the concentration of GC2-GH or its homologues bound to an upstream motif or cis element.
  • agents can be used in the study of glaucoma pathogenesis.
  • agents can also be used in the study of glaucoma prognosis.
  • such agents can be used in the treatment of glaucoma.
  • PEA 3 binding motifs or cis elements have been identified (Martin et al, Proc. Natl. Acad. Sci. (USA) 85: 5839-5843 (1988), herein incorporated by reference; Gutman and Wasylyk, EMBO J. 7: 2241-2246 (1990), herein incorporated by reference).
  • the PEA3 protein is a transcription factor that is reported to interact with API like proteins (Martin et al, Proc. Natl Acad. Sci. (USA) 85: 5839-5843 (1988), herein incorporated by reference). Sequences corresponding to an upstream motif or cis element capable of binding PEA3 is set forth in Figure 1 at residues 4765-4769.
  • transcription of ⁇ GR molecules can be effected by agents capable of altering the biochemical properties or concentration of PEA3 or its homologues, including, but not limited to, the concentration of PEA3 or its homologues bound to an upstream motif or cis element.
  • agents capable of altering the biochemical properties or concentration of PEA3 or its homologues including, but not limited to, the concentration of PEA3 or its homologues bound to an upstream motif or cis element.
  • agents can be used in the study of glaucoma pathogenesis.
  • such agents can also be used in the study of glaucoma prognosis.
  • such agents can be used in the treatment of glaucoma.
  • Mammalian interspersed repetitive (MIR) is an element involved in the coding and processing sequences of mammalian genes.
  • the MIR element is at least 260 bp in length and numbers about 10 5 copies within the mammalian genome (Murnane et al, Nucleic Acids Research 15: 2837-2839 (1995), herein incorporated by reference).
  • a sequence corresponding to an MIR upstream motif or cis element is set forth in Figure 1 at residues 4759-4954.
  • transcription of ⁇ GR molecules can be effected by agents capable of altering the biochemical properties or concentration of nuclear factors or their homologues, including, but not limited to, the concentration of nuclear factors or their homologues bound to an MIR upstream motif or cis element.
  • agents can be used in the study of glaucoma pathogenesis.
  • such agents can also be used in the study of glaucoma prognosis.
  • such agents can be used in the treatment of glaucoma.
  • HNF-1 hepatocyte-specific nuclear factor
  • a sequence corresponding to an HNF-1 upstream motif or cis element is set forth in Figure 1 at residues 4923-4941.
  • transcription of ⁇ GR molecules can be effected by agents capable of altering the biochemical properties or concentration of HNF-1 or its homologues, including, but not limited to, the concentration of HNF-1 or its homologues bound to an HNF-1 upstream motif or cis element.
  • agents capable of altering the biochemical properties or concentration of HNF-1 or its homologues including, but not limited to, the concentration of HNF-1 or its homologues bound to an HNF-1 upstream motif or cis element.
  • agents can be used in the study of glaucoma pathogenesis.
  • such agents can also be used in the study of glaucoma prognosis.
  • such agents can be used in the treatment of glaucoma.
  • cis elements or upstream motifs have been associated with gene regulation by steroid and thyroid hormones (e.g. glucocorticoid and estrogen)(Beato, Cell 56: 335-344 (1989), herein incorporated by reference; Brent et al, Molecular Endocrinology 89:1996-2000 (1989), herein incorporated by reference; Glass et al, Cell 54: 313-323 (1988), herein incorporated by reference; Evans, Science 240: 889-895 (1988), herein incorporated by reference).
  • glucocorticoid and estrogen e.g. glucocorticoid and estrogen
  • Thyroid hormones are capable of regulating genes containing a thyroid receptor upstream motif or cis element (Glass et al, Cell 54: 313-323 (1988), herein incorporated by reference). Thyroid hormones can negatively regulate TIGR.
  • transcription of TIGR molecules can be effected by agents capable of altering the biochemical properties or concentration of molecules capable of binding a thyroid receptor upstream motif or cis element.
  • NFKB is a transcription factor that is reportedly associated with a number of biological processes including T-cell activation and cytokine regulation (Lenardo et al, Cell 58: 227-229 (1989), herein incorporated by reference). A consensus upstream motif or cis element capable of binding NFKB has been reported (Lenardo et al, Cell 58: 227-229 (1989)).
  • transcription of ⁇ GR molecules can be effected by agents capable of altering the biochemical properties or concentration of NFKB or its homologues, including, but not limited to, the concentration of NFKB or its homologues bound to an upstream motif or cis element.
  • agents capable of altering the biochemical properties or concentration of NFKB or its homologues including, but not limited to, the concentration of NFKB or its homologues bound to an upstream motif or cis element.
  • agents can be used in the study of glaucoma pathogenesis.
  • agents can also be used in the study of glaucoma prognosis.
  • such agents can be used in the treatment of glaucoma.
  • nucleic acid molecule may be sense, antisense or triplex oligonucleotides corresponding to any part of the ⁇ GR promoter, ⁇ GR cDNA, TIGR intron, ⁇ GR exon or ⁇ GR gene.
  • the TIGR promoter, or fragment thereof, of the present invention may be cloned into a suitable vector and utilized to promote the expression of a marker gene (e.g. firefly luciferase (de Wet, Mol Cell Biol 7: 725-737 (1987), herein incorporated by reference) or GUS (Jefferson et al, EMBO J. 6: 3901-3907 (1987), herein incorporated by reference)).
  • a ⁇ GR promoter may be cloned into a suitable vector and utilized to promote the expression of a ⁇ GR gene in a suitable eukaryotic or prokaryotic host cell (e.g. human trabecular cell, Chinese hamster cell, E. coli).
  • a ⁇ GR promoter may be cloned into a suitable vector and utilized to promote the expression of a homologous or heterologous gene in a suitable eukaryotic or prokaryotic host cells (e.g. human trabecular cell lines, Chinese hamster cells, E. coli).
  • a suitable eukaryotic or prokaryotic host cells e.g. human trabecular cell lines, Chinese hamster cells, E. coli.
  • the TIGR promoter or any portion thereof of the present invention may be used in a gel-retardation or band shift assay (Old and Primrose, In Principles of Gene Manipulation: An Introduction To Genetic Engineering, Blackwell (1994)). Any of the cis elements identified in the present invention may be used in a gel- retardation or band shift assay to isolate proteins capable of binding the cis element.
  • Suitable DNA fragments or molecules comprise or consist of one or more of the following: sequences corresponding to an upstream motif or cis element characteristic of PRL-FP111 as set forth in Figure 1 at residues 370-388, and 4491- 4502, respectively, a sequence corresponding to an upstream motif or cis element capable of binding GR/PR as set forth in Figure 1 at residues 433-445, sequences corresponding to an upstream shear stress motif or cis element as set forth in Figure 1 at residues 446-451, 1288-1293, 3597-3602, 4771-4776, and 5240-5245, respectively, sequences corresponding to glucocorticoid response upstream motif or cis element as set forth in Figure 1 at residues 574-600, 1042-1056, 2444-2468, 2442-2269, 3536- 3563, 4574-4593, 4595-4614, 4851-4865, 4844-4864, 5079-5084, 5083-5111, respectively, a sequence corresponding to an up
  • a preferred class of agents of the present invention comprises nucleic acid molecules will encode all or a fragment of "TIGR promoter" or flanking gene sequences.
  • ⁇ GR promoter or “promoter” is used in an expansive sense to refer to the regulatory sequence(s) that control mRNA production. Such sequences include RNA polymerase binding sites, glucocorticoid response elements, enhancers, etc. All such ⁇ GR molecules may be used to diagnose the presence of glaucoma and severity of glaucoma. Such molecules may be either DNA or RNA.
  • Fragment nucleic acid molecules may encode significant portion(s) of, or indeed most of, SEQ ID NO: 1 or SEQ ID NO: 3 or SEQ ID NO: 4 or SEQ ID NO: 5.
  • the fragments may comprise smaller oligonucleotides (having from about 15 to about 250 nucleotide residues, and more preferably, about 15 to about 30 nucleotide residues.).
  • Such oligonucleotides include SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25.
  • oligonucleotides may derive from either the TIGR promoter, ⁇ GR introns, ⁇ GR exons, ⁇ GR cDNA and ⁇ GR downstream sequences comprise or consist of one or more of the following: sequences corresponding to an upstream motif or cis element characteristic of PRL-FP111 as set forth in Figure 1 at residues 370-388, and 4491-4502, respectively, a sequence corresponding to an upstream motif or cis element capable of binding GR/PR as set forth in Figure 1 at residues 433-445, sequences corresponding to an upstream shear stress motif or cis element as set forth in Figure 1 at residues 446-451, 1288-1293, 3597-3602, 4771-4776, and 5240-5245, respectively, sequences corresponding to glucocorticoid response upstream motif or cis element as set forth in Figure 1 at residues 574-600, 1042-1056, 2444-2468, 2442-2269, 3536-3563, 4574-
  • nucleic acid molecules are said to be capable of specifically hybridizing to one another if the two molecules are capable of forming an anti-parallel, double-stranded nucleic acid structure, whereas they are unable to form a double-stranded structure when incubated with a non-TIGR nucleic acid molecule.
  • a nucleic acid molecule is said to be the "complement” of another nucleic acid molecule if they exhibit complete complementarity.
  • molecules are said to exhibit "complete complementarity" when every nucleotide of one of the molecules is complementary to a nucleotide of the other.
  • Two molecules are said to be “minimally complementary” if they can hybridize to one another with sufficient stability to permit them to remain annealed to one another under at least conventional "low-stringency” conditions. Similarly, the molecules are said to be “complementary” if they can hybridize to one another with sufficient stability to permit them to remain annealed to one another under conventional "high- stringency” conditions.
  • oligonucleotides may be employed to obtain other ⁇ GR nucleic acid molecules.
  • Such molecules include the TIGR-encoding nucleic acid molecule of non-human animals (particularly, cats, monkeys, rodents and dogs), fragments thereof, as well as their promoters and flanking sequences.
  • Such molecules can be readily obtained by using the above- described primers to screen cDNA or genomic libraries obtained from non-human species. Methods for forming such libraries are well known in the art.
  • Such analogs may differ in their nucleotide sequences from that of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, or from molecules consisting of sequences corresponding to an upstream motif or cis element characteristic of PRL-FP111 as set forth in Figure 1 at residues 370-388, and 4491-4502, respectively, a sequence corresponding to an upstream motif or cis element capable of binding GR/PR as set forth in Figure 1 at residues 433-445, sequences
  • SEQ ID NO: 1 SEQ ID NO: 2
  • SEQ ID NO: 3 SEQ ID NO: 4
  • SEQ ID NO: 5 SEQ ID NO: 6
  • SEQ ID NO: 7 SEQ ID NO: 8
  • SEQ ID NO: 9 SEQ ID NO: 10
  • SEQ ID NO: 11 SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14,
  • SEQ ID NO: 15 SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, sequences corresponding to an upstream motif or cis element characteristic of PRL-FP111 as set forth in Figure 1 at residues 370-388, and 4491-4502, respectively, a sequence corresponding to an upstream motif or cis element characteristic of PRL-FP111 as set forth in Figure 1 at residues 370-388, and 4491-4502, respectively, a sequence corresponding
  • the TIGR promoter sequence(s) and ⁇ GR flanking sequences can also be obtained by incubating oligonucleotide probes of TIGR oligonucleotides with members of genomic human libraries and recovering clones that hybridize to the probes.
  • methods of "chromosome walking," or 3' or 5' RACE may be used (Frohman, M.A. et al, Proc. Natl. Acad. Sci. (U.S.A.) S5:8998-9002 (1988), herein incorporated by reference); Ohara, O. et al, Proc. Natl Acad. Sci. (U.S.A.) 86:5673-5677 (1989), herein incorporated by reference) to obtain such sequences.
  • a particularly desired use of the present invention relates to the diagnosis of glaucoma, POAG, pigmentary glaucoma, high tension glaucoma and low tension glaucoma and their related diseases.
  • Another particularly desired use of the present invention relates to the prognosis of glaucoma, POAG, pigmentary glaucoma, high tension glaucoma and low tension glaucoma and their related diseases.
  • glaucoma includes both primary glaucomas, secondary glaucomas, juvenile glaucomas, congenital glaucomas, and familial glaucomas, including, without limitation, pigmentary glaucoma, high tension glaucoma and low tension glaucoma and their related diseases.
  • methods for diagnosing or prognosing glaucoma suffer from inaccuracy, or require multiple examinations.
  • the molecules of the present invention may be used to define superior assays for glaucoma.
  • the molecules of the present invention may be used to diagnosis or predict an individual's sensitivity to elevated intraocular pressure upon administration of steroids such as glucocorticoids or corticosteroids, or anti-inflammatory steroids).
  • steroids such as glucocorticoids or corticosteroids, or anti-inflammatory steroids.
  • Dexamethasone, cortisol and prednisolone are preferred steroids for this purpose.
  • Medical conditions such as inflammatory and allergic disorders, as well as organ transplantation recipients, benefit from treatment with glucocorticoids.
  • Certain individuals exhibit an increased sensitivity to such steroids (i.e., "steroid sensitivity"), which is manifested by an undesired increase in intraocular pressure.
  • the present invention may be employed to diagnosis or predict such sensitivity, as well as glaucoma and related diseases.
  • the ⁇ GR molecules of the present invention are used to determine whether an individual has a mutation affecting the level (i.e., the concentration of TIGR mRNA or protein in a sample, etc.) or pattern (i.e., the kinetics of expression, rate of decomposition, stability profile, etc.) of the ⁇ GR expression (collectively, the " ⁇ GR response" of a cell or bodily fluid) (for example, a mutation in the TIGR gene, or in a regulatory region(s) or other gene(s) that control or affect the expression of ⁇ GR), and being predictive of individuals who would be predisposed to glaucoma (prognosis), related diseases, or steroid sensitivity.
  • a mutation affecting the level i.e., the concentration of TIGR mRNA or protein in a sample, etc.
  • pattern i.e., the kinetics of expression, rate of decomposition, stability profile, etc.
  • the ⁇ GR response for example, a mutation in the TIGR gene, or
  • the ⁇ GR response manifested by a cell or bodily fluid is said to be "altered” if it differs from the ⁇ GR response of cells or of bodily fluids of normal individuals. Such alteration may be manifested by either abnormally increased or abnormally diminished ⁇ GR response.
  • the ⁇ GR response manifested by the cell or bodily fluid of the patient is compared with that of a similar cell sample (or bodily fluid sample) of normal individuals.
  • such an analysis is conducted by determining the presence and /or identity of polymorphism(s) in the TIGR gene or its flanking regions which are associated with glaucoma, or a predisposition (prognosis) to glaucoma, related diseases, or steroid sensitivity.
  • ⁇ GR flanking regions refers to those regions which are located either upstream or downstream of the ⁇ GR coding region. Any of a variety of molecules can be used to identify such polymorphism(s).
  • SEQ ID NO: 1 SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, sequences corresponding to an upstream motif or cis element characteristic of PRL- FP111 as set forth in Figure 1 at residues 370-388, and 4491-4502, respectively, a sequence corresponding to an upstream motif or cis element capable of binding GR/PR as set forth in Figure 1 at residues 433-445, sequences corresponding to an upstream shear stress motif or cis element as set forth in
  • such polymorphisms can be detected through the use of a marker nucleic acid molecule or a marker protein that is genetically linked to (i.e., a polynucleotide that co-segregates with) such polymorphism(s).
  • a marker nucleic acid molecule or a marker protein that is genetically linked to i.e., a polynucleotide that co-segregates with
  • the TIGR gene and/or a sequence or sequences that specifically hybridize to the ⁇ GR gene have been mapped to chromosome lq, 21-32, and more preferably to the ⁇ GR gene located at chromosome 1, q21-27, and more preferably to the TIGR gene located at chromosome 1, q22-26, and most preferably to the ⁇ GR gene located at chromosome 1, q24.
  • such marker nucleic acid molecules will have the nucleotide sequence of a polynucleotide that is closely genetically linked to such polymorphism(s) (e.g., markers located at chromosome 1, ql9-25 (and more preferably chromosome 1, q23-25, and most preferably chromosome 1, q24. Localization studies using a Stanford G3 radiation hybrid panel mapped the nucleotide sequence of a polynucleotide that is closely genetically linked to such polymorphism(s) (e.g., markers located at chromosome 1, ql9-25 (and more preferably chromosome 1, q23-25, and most preferably chromosome 1, q24. Localization studies using a Stanford G3 radiation hybrid panel mapped the
  • TIGR gene with the D1S2536 marker nucleic acid molecules at the D1S2536 locus with a LOD score of 6.0.
  • Other marker nucleic acid molecules in this region include: D1S210; D1S1552; D1S2536; D1S2790; SHGC-12820; and D1S2558.
  • Other polynucleotide markers that map to such locations are known and can be employed to identify such polymorphism(s).
  • a "polymorphism" in the ⁇ GR gene or its flanking regions is a variation or difference in the sequence of the ⁇ GR gene or its flanking regions that arises in some of the members of a species.
  • the variant sequence and the "original" sequence co-exist in the species' population. In some instances, such co-existence is in stable or quasi-stable equilibrium.
  • a polymorphism is thus said to be "allelic,” in that, due to the existence of the polymorphism, some members of a species may have the original sequence (i.e. the original "allele") whereas other members may have the variant sequence (i.e. the variant "allele”). In the simplest case, only one variant sequence may exist, and the polymorphism is thus said to be di-allelic. In other cases, the species' population may contain multiple alleles, and the polymorphism is termed tri-allelic, etc.
  • a single gene may have multiple different unrelated polymorphisms. For example, it may have a di-allelic polymorphism at one site, and a multi-allelic polymorphism at another site.
  • the variation that defines the polymorphism may range from a single nucleotide variation to the insertion or deletion of extended regions within a gene.
  • the DNA sequence variations are in regions of the genome that are characterized by short tandem repeats (STRs) that include tandem di- or tri- nucleotide repeated motifs of nucleotides.
  • STRs short tandem repeats
  • Polymorphisms characterized by such tandem repeats are referred to as "variable number tandem repeat" (“VNTR”) polymorphisms.
  • VNTRs have been used in identity and paternity analysis (Weber, J.L., U.S. Patent 5,075,217; Armour, J.A.L. et al, FEBS Lett. 307:113-115 (1992); Jones, L.
  • such polymorphisms can be detected through the use of a marker nucleic acid molecule that is physically linked to such polymorphism(s).
  • marker nucleic acid molecules comprising a nucleotide sequence of a polynucleotide located within 1 mb of the polymorphism(s), and more preferably within 100 kb of the polymorphism(s), and most preferably within 10 kb of the polymorphism(s) can be employed.
  • marker nucleic acids examples include SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: ' 22, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25.
  • a marker nucleic acid in another embodiment, is capable of specifically detecting TIGRmtl, TIGRmt2, TIGRmt3, TIGRmt4, TIGRmt5, TIGRsvl,o ⁇ a combination of these mutations.
  • Methods to detect base(s) substitutions, base(s) deletions and base(s) additions are known in the art (i.e. methods to genotype an individual). For example, "Genetic Bit Analysis ("GBA”) method is disclosed by Goelet, P. et al, WO 92/15712, herein incorporated by reference, may be used for detecting the single nucleotide polymorphisms of the present invention.
  • GBA is a method of polymorphic site interrogation in which the nucleotide sequence information surrounding the site of variation in a target DNA sequence is used to design an oligonucleotide primer that is complementary to the region immediately adjacent to, but not including, the variable nucleotide in the target DNA.
  • the target DNA template is selected from the biological sample and hybridized to the interrogating primer.
  • This primer is extended by a single labeled dideoxynucleotide using DNA polymerase in the presence of two, and preferably all four chain terminating nucleoside triphosphate precursors.
  • the detection of polymorphic sites in a sample of DNA may be facilitated through the use of nucleic acid amplification methods. Such methods specifically increase the concentration of polynucleotides that span the polymorphic site, or include that site and sequences located either distal or proximal to it. Such amplified molecules can be readily detected by gel electrophoresis or other means.
  • PCR polymerase chain reaction
  • LCR Ligase Chain Reaction
  • LCR can be performed with oligonucleotides having the proximal and distal sequences of the same strand of a polymorphic site.
  • either oligonucleotide will be designed to include the actual polymorphic site of the polymorphism.
  • the reaction conditions are selected such that the oligonucleotides can be ligated together only if the target molecule either contains or lacks the specific nucleotide that is complementary to the polymorphic site present on the oligonucleotide.
  • the oligonucleotides may be selected such that they do not include the polymorphic site (see, Segev, D., PCT Application WO 90/01069).
  • OLA Oligonucleotide Ligation Assay
  • nucleic acid amplification procedures such as allele-specific oligomers, branched DNA technology, transcription-based amplification systems, or isothermal amplification methods may also be used to amplify and analyze such polymorphisms (Malek, L.T. et al, U.S. Patent 5,130,238; Davey, C. et al, European Patent Application 329,822; Schuster et al, U.S. Patent 5,169,766; Miller, H.I. et al, PCT appln. WO 89/06700; Kwoh, D. et al, Proc. Natl. Acad. Sci.
  • the identification of a polymorphism in the ⁇ GR gene can be determined in a variety of ways. By correlating the presence or absence of glaucoma in an individual with the presence or absence of a polymorphism in the ⁇ GR gene or its flanking regions, it is possible to diagnose the predisposition (prognosis) of an asymptomatic patient to glaucoma, related diseases, or steroid sensitivity. If a polymorphism creates or destroys a restriction endonuclease cleavage site, or if it results in the loss or insertion of DNA (e.g., a VNTR polymorphism), it will alter the size or profile of the DNA fragments that are generated by digestion with that restriction endonuclease.
  • RFLPs restriction fragment length polymorphisms
  • RFLPs have been widely used in human and animal genetic analyses (Glassberg, J., UK patent Application 2135774; Skolnick, M.H. et al, Cytogen. Cell Genet. 32:58-67 (1982); Botstein, D. et al, Ann. J. Hum. Genet. 32:314-331 (1980); Fischer, S.G et al. (PCT Application WO90/13668); Uhlen, M., PCT Application WO90/11369)).
  • the role of ⁇ GR in glaucoma pathogenesis indicates that the presence of genetic alterations (e.g., DNA polymorphisms) that affect the ⁇ GR response can be employed to predict glaucoma
  • a preferred method of achieving such identification employs the single- strand conformational polymorphism (SSCP) approach.
  • the SSCP technique is a method capable of identifying most sequence variations in a single strand of DNA, typically between 150 and 250 nucleotides in length (Elles, Methods in Molecular Medicine: Molecular Diagnosis of Genetic Diseases, Humana Press (1996), herein incorporated by reference); Orita et al, Genomics 5: 874-879 (1989), herein incorporated by reference). Under denaturing conditions a single strand of DNA will adopt a conformation that is uniquely dependent on its sequence conformation. This conformation usually will be different, even if only a single base is changed.
  • a sample DNA is obtained from a patient's cells.
  • the DNA sample is obtained from the patient's blood.
  • any source of DNA may be used.
  • the DNA is subjected to restriction endonuclease digestion.
  • ⁇ GR is used as a probe in accordance with the above-described RFLP methods. By comparing the RFLP pattern of the ⁇ GR gene obtained from normal and glaucomatous patients, one can determine a patient's predisposition (prognosis) to glaucoma. The polymorphism obtained in this approach can then be cloned to identify the mutation at the coding region which alters the protein's structure or regulatory region of the gene which affects its expression level.
  • Changes involving promoter interactions with other regulatory proteins can be identified by, for example, gel shift assays using HTM cell extracts, fluid from the anterior chamber of the eye, serum, etc. Interactions of TIGR protein in glaucomatous cell extracts, fluid from the anterior chamber of the eye, serum, etc. can be compared to control samples to thereby identify changes in those properties of TIGR that relate to the pathogenesis of glaucoma. Similarly such extracts and fluids as well as others (blood, etc.) can be used to diagnosis or predict steroid sensitivity.
  • polymorphisms may be identified through such methods. Examples of such classes include: (1) polymorphisms present in the ⁇ GR cDNA of different individuals; (2) polymorphisms in non-translated TIGR gene sequences, including the promoter or other regulatory regions of the ⁇ GR gene; (3) polymorphisms in genes whose products interact with ⁇ GR regulatory sequences; (4) polymorphisms in gene sequences whose products interact with the TIGR protein, or to which the ⁇ GR protein binds.
  • the evaluation is conducted using oligonucleotide "probes" whose sequence is complementary to that of a portion of SEQ ID NO: 1, SEQ ID NO: 2 SEQ ID NO: 3, SEQ ID NO: 4, or SEQ ID NO: 5. Such molecules are then incubated with cell extracts of a patient under conditions sufficient to permit nucleic acid hybridization.
  • glaucoma could be diagnosed or predicted by determining whether the administration of a glucocorticoid (administered topically, intraocularly, intramuscularly, systemically, or otherwise) alters the ⁇ GR response of a particular individual, relative to that of normal individuals.
  • a ⁇ GR gene-inducing amount of the glucocorticoid will be provided.
  • a ⁇ GR gene-inducing amount of a glucocorticoid is an amount of glucocorticoid sufficient to cause a detectable induction of ⁇ GR expression in cells of glaucomatous or non-glaucomatous individuals.
  • the agents of the present invention can be formulated according to known methods to prepare pharmacologically acceptable compositions, whereby these materials, or their functional derivatives, having the desired degree of purity are combined in admixture with a physiologically acceptable carrier, excipient, or stabilizer. Such materials are non-toxic to recipients at the dosages and concentrations employed.
  • the active component of such compositions may be agents analogs or mimetics of such molecules. Where nucleic acid molecules are employed, such molecules may be sense, antisense or triplex oligonucleotides of the TIGR promoter, ⁇ GR cDNA, ⁇ GR intron, ⁇ GR exon or ⁇ GR gene.
  • a composition is said to be "pharmacologically acceptable” if its administration can be tolerated by a recipient patient.
  • An agent is physiologically significant if its presence results in a detectable change in the physiology of a recipient patient.
  • Suitable vehicles and their formulation, inclusive of other human proteins, e.g., human serum albumin, are described, for example, in Remington's Pharmaceutical Sciences (16th ed., Osol, A., Ed., Mack, Easton PA (1980)).
  • a buffer such as phosphate or other organic acid salt preferably at a pH of about 7 to 8.
  • the composition is only partially soluble in water, it may be prepared as a microemulsion by formulating it with a nonionic surfactant such as Tween, Pluronics, or PEG, e.g., Tween 80, in an amount of, for example, 0.04-0.05% (w/v), to increase its solubility.
  • a nonionic surfactant such as Tween, Pluronics, or PEG, e.g., Tween 80, in an amount of, for example, 0.04-0.05% (w/v), to increase its solubility.
  • water soluble as applied to the polysaccharides and polyethylene glycols is meant to include colloidal solutions and dispersions.
  • solubility of the cellulose derivatives is determined by the degree of substitution of ether groups, and the stabilizing derivatives useful herein should have a sufficient quantity of such ether groups per anhydroglucose unit in the cellulose chain to render the derivatives water soluble.
  • a degree of ether substitution of at least 0.35 ether groups per anhydroglucose unit is generally sufficient.
  • the cellulose derivatives may be in the form of alkali metal salts, for example, the Li, Na, K or Cs salts.
  • antioxidants e.g., ascorbic acid
  • low molecular weight polypeptides e.g., polyarginine or tripeptides
  • proteins such as serum albumin, gelatin, or immunoglobulins
  • hydrophilic polymers such as polyvinyl pyrrolidone
  • amino acids such as glycine, glutamic acid, aspartic acid, or arginine
  • monosaccharides, disaccharides, and other carbohydrates including cellulose or its derivatives, glucose, mannose, or dextrins
  • chelating agents such as EDTA
  • sugar alcohols such as mannitol or sorbitol.
  • Controlled or sustained release preparations may be achieved through the use of polymers to complex or absorb the ⁇ GR molecule(s) of the composition.
  • the controlled delivery may be exercised by selecting appropriate macromolecules (for example polyesters, polyamino acids, polyvinyl pyrrolidone, ethylenevinylacetate, methylcellulose, carboxymethylcellulose, or protamine sulfate) and the concentration of macromolecules as well as the methods of incorporation in order to control release.
  • Sustained release formulations may also be prepared, and include the formation of microcapsular particles and implantable articles.
  • the TIGR molecule(s) of the composition is preferably incorporated into a biodegradable matrix or microcapsule.
  • a suitable material for this purpose is a polylactide, although other polymers of poly-(a- hydroxycarboxylic acids), such as poly-D-(-)-3-hydroxybutyric acid (EP 133,988A), can be used.
  • Other biodegradable polymers include poly(lactones), poly(orthoesters), polyamino acids, hydrogels, or poly(orthocarbonates) poly(acetals).
  • the polymeric material may also comprise polyesters, poly(lactic acid) or ethylene vinylacetate copolymers.
  • sustained release compositions see U.S. Patent No. 3,773,919, EP 58,481A, U.S. Patent No. 3,887,699, EP 158,277 A, Canadian Patent No. 1176565, Sidman, U. et al, Biopolymers 22:547 (1983), and Langer, R. et al, Chem. Tech. 12:98 (1982).
  • microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, for example, hydroxymethylcellulose or gelatine-microcapsules and poly(methylmethacylate) microcapsules, respectively, or in colloidal drug delivery systems, for example, liposomes, albumin microspheres, microemulsions, nanoparticles, and nanocapsules or in macroemulsions.
  • colloidal drug delivery systems for example, liposomes, albumin microspheres, microemulsions, nanoparticles, and nanocapsules or in macroemulsions.
  • liposome formulations and methods that permit intracellular uptake of the molecule will be employed. Suitable methods are known in the art, see, for example, Chicz, R.M. et al. (PCT Application WO 94/04557), Jaysena, S.D. et al. (PCT Application W093/12234), Yarosh, D.B. (U.S. Patent No. 5,190,762), Callahan, M.V. et al. (U.S. Patent No. 5,270,052) and Gonzalezro, R.J. (PCT Application 91/05771), all herein incorporated by reference.
  • SSCP Single strand conformational polymorphism
  • primers are constructed: forward primer “Sk-la”: 5'-TGA GGC TTC CTC TGG AAA C-3' (SEQ ID NO: 6); reverse primer “ca2”: 5'- TGA AAT CAG CAC ACC AGT AG-3' (SEQ ID NO: 7); forward primer “CA2”: 5'- GCA CCC ATA CCC CAA TAA TAG-3' (SEQ ID NO: 8); reverse primer “Pr+1”: 5'- AGA GTT CCC CAG ATT TCA CC-3' (SEQ ID NO: 9); forward primer "Pr-1”: 5'- ATC TGG GGA ACT CTT CTC AG-3' (SEQ ID NO: 10); reverse primer "Pr+2(4A2)”: 5'-TAC AGT TGT TGC AGA TAC G-3' (SEQ ID NO: 11); forward primer "Pr- 2(4A)”: 5'-ACA ACG TAT CTG CAA CAA CTG-3' (SEQ ID NO: 12);
  • the locations of primers: Sk-la, ca2, CA2, Pr+1, Pr-1, Pr+2(4A2), Pr-2(4A), Pr+3(4A), Pr-3 (4A), Pr-3(4A), Pr+2(4A1), and Pr+1(4A) are diagramatically set forth in Figure 4.
  • the location of primers: KSIX, SK1XX, Ks2al, SK3, KS4, SK6A, KS5, SK8, and KS6 are diagramatically set forth in Figure 5.
  • SSCP primers SK-la, ca2, CA2, Pr+1, Pr-2(4A), Pr+3(4A), SK1XX, and KS6 detect single strand conformational polymorphisms in this population.
  • An SSCP is detected using SSCP primers Pr+3(4A) and Pr-2(4A). 70 family members of the Klamath Fall, Oregon are screened with these primers and the results are set forth in Table 1.
  • a second SSCP is detected using SSCP primers Pr+1 and CA2. 14 family members of the Klamath Fall, Oregon are screened with these primers. A characteristic polymorphism is found in the 6 affected family members but absent in the 8 unaffected members.
  • a third SSCP is detected using SSCP primers ca2 and sk- la. The same 14 family members of the Klamath Fall, Oregon that are screened with Pr+1 and CA2 are screened with ca2 and sk-la primers. A characteristic polymorphism is found in the 6 affected family members but absent in the 8 unaffected members.
  • a fourth SSCP is detected using SSCP primers KS6 and SK1XX. 22 family members of the Klamath Fall, Oregon and 10 members of a Portland, Oregon pedigree are screened with these primers. A polymorphism is found in exon 3. The results are as set forth in Table 2.
  • myocilin A novel myosin-like acidic protein termed myocilin is expressed predominantly in the photoreceptor cells of retina and is localized particularly in the rootlet and basal body of connecting cilium (Kubota et al, Genomics 41: 360-369 (1997), herein incorporated by reference).
  • the myocilin gene is mapped to human chromosome Iq23-q24.
  • the coding region of myocilin is 100 percent homologous with TIGR.
  • Homology searches are performed by GCG (Genetics Computer Group, Madison, WI) and include the GenBank, EMBL, Swiss-Prot databases and EST analysis. Using the Blast search, the best fits are found with a stretch of 177 amino acids in the carboxy terminals for an extracellular mucus protein of the olfactory, olfactomedin and three olfactomedin-like species.
  • the alignment presented in Figure 6 shows the ⁇ GR homology (SEQ ID NO. 27) to an expressed sequence tag (EST) sequence from human brain (ym08hl2.rl)(SEQ ID NO.
  • CTCAAAGTGG TAATAACAGT ACCTGTGATT TTGTCATTAC CAATAGAAAT CACAGACATT 4380
  • TAGGAACTAT TATTGGGGTA TGGGTGCATA AATTGGGATG TTCTTTTTAA AAAGAAACTC 5100
  • CTCAAAGTGG TAATAAGAGT ACCTGTGATT TTGTCATTAC CAATAGAAAT CACAGACATT 4380
  • TAGGAACTAT TATTGGGGTA TGGGTGCATA AATTGGGATG TTCTTTTTAA AAAGAAACTC 5100
  • Glu Lys Glu lie Pro Gly Ala Gly Tyr His Gly Gin Phe Pro Tyr Ser
  • Trp Val lie Tyr Ser Thr Asp Glu Ala Lys Gly Ala lie Val Leu Ser 65 70 75 80
  • MOLECULE TYPE protein
  • FRAGMENT TYPE N-terminal

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Abstract

Dans un écran à plasma à courant alternatif, un dispositif d'interface informatique permettant d'assurer l'interface du signal rouge-vert-bleu (RVB) entre une mémoire de trame et des électrodes d'adressage supérieures et inférieures attaquant les microcircuits. Le dispositif d'interface informatique comprend des microcircuits d'interface de données supérieures et inférieures assurant l'interface avec les microcircuits. Ces microcircuits sont compatibles les uns avec les autres grâce à une logique identique. Chaque microcircuit comprend une partie de mappage de données permettant de stocker provisoirement les données RVB transférées depuis la mémoire de trame dans un agencement convenant à un agencement de pixels d'un écran à plasma et de produire des données RVB en parallèle dans un premier et un second ordre qui est inversé par rapport au premier ordre. Chaque microcircuit comprend aussi une zone de sélection de données de sortie permettant de sélectionner les données RVB du premier ou second ordre et de les considérer comme données de sortie. Le dispositif d'interface informatique comprend en outre une zone de synchronisation de sortie permettant d'obtenir de manière synchronisée les données RVB qui sont transférées en parallèle à partir de la zone de sélection de données.
PCT/US1998/000468 1997-01-28 1998-01-09 Dispositif d'interface informatique pour ecran a plasma de type ca WO1998032850A1 (fr)

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EP98901761A EP1012271B1 (fr) 1997-01-28 1998-01-09 Procedes de diagnostic, de pronostic et de traitement du glaucome et de troubles associes
JP53201798A JP2001509669A (ja) 1997-01-28 1998-01-09 緑内障および関連疾患の診断、予知および治療方法
CA002278782A CA2278782C (fr) 1997-01-28 1998-01-09 Procedes de diagnostic, de pronostic et de traitement du glaucome et de troubles associes
AU58204/98A AU742405B2 (en) 1997-01-28 1998-01-09 Methods for the diagnosis, prognosis and treatment of glaucoma and related disorders
NZ336860A NZ336860A (en) 1997-01-28 1998-01-09 Diagnosis, prognosis and treatment of glaucoma and related disorders using polynucleotides hybridised to a TIGR promoter
DE69838553T DE69838553T2 (de) 1997-01-28 1998-01-09 Verfahren zur diagnose, prognose und behandlung von glaukom und verwandten erkrankungen
NO993653A NO993653L (no) 1997-01-28 1999-07-27 FremgangsmÕte for diagnose, prognose og behandling av glaukom og relaterte sykdommer

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999051779A2 (fr) * 1998-04-07 1999-10-14 The University Of Iowa Research Foundation Traitement et diagnostic du glaucome
WO2000042220A1 (fr) * 1999-01-11 2000-07-20 The Regents Of The University Of California Acides nucleiques, kits, et methodes de diagnostic, de pronostic, et de traitement du glaucome et des troubles associes
US6171788B1 (en) 1997-01-28 2001-01-09 The Regents Of The University Of California Methods for the diagnosis, prognosis and treatment of glaucoma and related disorders
WO2001088120A1 (fr) * 2000-05-17 2001-11-22 Tsubota Ltd. Gene associe au glaucome a angle ouvert, y compris le glaucome a tension oculaire normale
US6956103B2 (en) 1994-04-28 2005-10-18 The University Of Iowa Research Foundation Glaucoma therapeutics and diagnostics
US7138511B1 (en) 1997-01-28 2006-11-21 The Regents Of The University Of California Nucleic acids, kits and methods for the diagnosis, prognosis and treatment of glaucoma and related disorders
WO2020118293A3 (fr) * 2018-12-07 2020-07-23 Georgia Tech Research Corporation Anticorps qui se lient à la myociline pliée de manière native

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20020168639A1 (en) * 2000-09-22 2002-11-14 Muraca Patrick J. Profile array substrates
US20030119000A1 (en) * 2001-11-05 2003-06-26 Jon Polansky Methods to screen and treat individuals with glaucoma or the propensity to develop glaucoma
US6727354B2 (en) * 2001-12-12 2004-04-27 Quest Diagnostics Investments, Inc. Compositions and methods for TIGR genotyping assays

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996014411A1 (fr) * 1994-11-03 1996-05-17 The Regents Of The University Of California Procedes de diagnostic du glaucome

Family Cites Families (48)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3887699A (en) 1969-03-24 1975-06-03 Seymour Yolles Biodegradable polymeric article for dispensing drugs
US3773919A (en) 1969-10-23 1973-11-20 Du Pont Polylactide-drug mixtures
JPS57501692A (fr) 1980-09-24 1982-09-16
PH19942A (en) 1980-11-18 1986-08-14 Sintex Inc Microencapsulation of water soluble polypeptides
IE52535B1 (en) 1981-02-16 1987-12-09 Ici Plc Continuous release pharmaceutical compositions
US4582788A (en) 1982-01-22 1986-04-15 Cetus Corporation HLA typing method and cDNA probes used therein
DE3381518D1 (de) 1982-01-22 1990-06-07 Cetus Corp Verfahren zur charakterisierung von hla und die darin benutzten cdns-testmittel.
IL71064A (en) 1983-02-28 1989-10-31 Lifecodes Corp Paternity and forensic test involving analysis of dna polymorphic genetic regions
US4617299A (en) 1983-12-19 1986-10-14 Knepper Paul A Method for the prevention of ocular hypertension, treatment of glaucoma and treatment of ocular hypertension
DE3413608A1 (de) 1984-04-11 1985-10-24 Hoechst Ag, 6230 Frankfurt Implantierbare zubereitungen von regulatorischen peptiden mit gesteuerter freisetzung und verfahren zu ihrer herstellung
US4683194A (en) 1984-05-29 1987-07-28 Cetus Corporation Method for detection of polymorphic restriction sites and nucleic acid sequences
US4683202A (en) 1985-03-28 1987-07-28 Cetus Corporation Process for amplifying nucleic acid sequences
US4757089A (en) 1985-06-14 1988-07-12 Massachusetts Eye And Ear Infirmary Increasing aqueous humor outflow
CA1284931C (fr) 1986-03-13 1991-06-18 Henry A. Erlich Procede de detection de variations specifiques de nucleotides et de polymorphismes genetiques dans les acides nucleiques
GB8606719D0 (en) 1986-03-19 1986-04-23 Lister Preventive Med Genetic probes
DE3612537C1 (de) 1986-04-14 1987-07-16 Dispersa Ag Arzneimittel zur Behandlung von Entzuendungen im Auge
CA1338457C (fr) 1986-08-22 1996-07-16 Henry A. Erlich Enzyme thermostable purifiee
IL86724A (en) 1987-06-19 1995-01-24 Siska Diagnostics Inc Methods and kits for amplification and testing of nucleic acid sequences
EP0359789B1 (fr) 1988-01-21 1993-08-04 Genentech, Inc. Amplification et detection de sequences d'acides nucleiques
IE63392B1 (en) 1988-02-08 1995-04-19 Insite Vision Inc Ophthalmic suspensions
US5192535A (en) 1988-02-08 1993-03-09 Insite Vision Incorporated Ophthalmic suspensions
CA1340807C (fr) 1988-02-24 1999-11-02 Lawrence T. Malek Procede d'amplification d'une sequence d'acide nucleique
US5130238A (en) 1988-06-24 1992-07-14 Cangene Corporation Enhanced nucleic acid amplification process
US5190762A (en) 1988-07-06 1993-03-02 Applied Genetics, Inc. Method of administering proteins to living skin cells
WO1990001069A1 (fr) 1988-07-20 1990-02-08 Segev Diagnostics, Inc. Procede d'amplification et de detection de sequences d'acide nucleique
GB2228086A (en) 1988-11-25 1990-08-15 Ici Plc Characterisation of genomic DNA
KR920700360A (ko) 1989-03-22 1992-02-19 하리크 프리드리히 미끄럼 베어링
US5075217A (en) 1989-04-21 1991-12-24 Marshfield Clinic Length polymorphisms in (dC-dA)n ·(dG-dT)n sequences
AU5645690A (en) 1989-05-05 1990-11-29 Lifecodes Corporation Method for genetic analysis of a nucleic acid sample
AU6521790A (en) 1989-10-13 1991-05-16 Hans Schreier Lipophilic acylpyrazinamide prodrugs
US5124154A (en) 1990-06-12 1992-06-23 Insite Vision Incorporated Aminosteroids for ophthalmic use
US5270052A (en) 1991-04-19 1993-12-14 New England Medical Center Hospitals, Inc. Methods and compositions for treatment of infection by intracellular parasites
US5169766A (en) 1991-06-14 1992-12-08 Life Technologies, Inc. Amplification of nucleic acid molecules
WO1993012234A1 (fr) 1991-12-13 1993-06-24 Sri International Reactifs antiviraux a base de proteines de liaison de l'arn
JPH08502244A (ja) 1992-08-11 1996-03-12 プレジデント アンド フェローズ オブ ハーバード カレッジ 免疫調節ペプチド
US5420120A (en) 1993-12-17 1995-05-30 Alcon Laboratories, Inc. Anti-inflammatory glucocorticoid compounds for topical ophthalmic use
US5474985A (en) 1993-12-22 1995-12-12 The Regents Of The University Of California Preventing and treating elevated intraocular pressure associated with administered or endogenous steroids using non-steroidal cyclooxygenase inhibitors
US5916778A (en) 1994-04-28 1999-06-29 University Of Iowa Research Foundation Diagnostics based on a glaucoma causing gene
US5885776A (en) 1997-01-30 1999-03-23 University Of Iowa Research Foundation Glaucoma compositions and therapeutic and diagnositic uses therefor
US5925748A (en) 1994-04-28 1999-07-20 The University Of Iowa Research Foundation DNA diagnostics for glaucoma
US5789169A (en) 1994-11-03 1998-08-04 Regents Of The University Of California Methods for the diagnosis of glaucoma
FR2733251B1 (fr) 1995-04-18 1997-07-04 Inst Nat Sante Rech Med Depistage du glaucome juvenile
US5599535A (en) 1995-06-07 1997-02-04 Regents Of The University Of California Methods for the cyto-protection of the trabecular meshwork
US5674888A (en) 1995-06-07 1997-10-07 University Of California Method for the treatment of a trabecular meshwork whose cells are subject to inhibition of cell division
CA2271235A1 (fr) 1996-11-08 1998-05-14 University Of Iowa Research Foundation Proteine associee au glaucome, acide nucleique correspondant et leurs utilisations diagnostiques et therapeutiques
US6171788B1 (en) 1997-01-28 2001-01-09 The Regents Of The University Of California Methods for the diagnosis, prognosis and treatment of glaucoma and related disorders
CA2216997A1 (fr) 1997-09-30 1999-03-30 Jean Morissette Diagnostic moleculaire des glaucomes associes aux chromosomes 1
AU9334098A (en) 1997-09-30 1999-04-23 Universite Laval Molecular diagnostic of glaucomas associated with chromosomes 1, and method of treatment thereof

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996014411A1 (fr) * 1994-11-03 1996-05-17 The Regents Of The University Of California Procedes de diagnostic du glaucome

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
ESCRIBANO J ET AL: "ISOLATION AND CHARACTERIZATION OF CELL-SPECIFIC CDNA CLONES FROM A SUBTRACTIVE LIBRARY OF THE OCULAR CILIARY BODY OF A SINGLE NORMAL HUMAN DONOR: TRANSCRIPTION AND SYNTHESIS OF PLASMA PROTEINS", JOURNAL OF BIOCHEMISTRY, vol. 118, no. 5, November 1995 (1995-11-01), pages 921 - 931, XP002049425 *
STONE E M ET AL: "IDENTIFICATION OF A GENE THAT CAUSED PRIMARY OPEN ANGLE GLAUCOMA", SCIENCE, vol. 275, 31 January 1997 (1997-01-31), pages 668 - 670, XP002049424 *
SUNDEN S L F ET AL: "FINE MAPPING OF THE AUTOSOMAL DOMINANT JUVENILE OPEN ANGLE GLAUCOMA (GLC1A) REGION AND EVALUATION OF CANDIDATE GENES", GENOME RESEARCH, vol. 6, no. 9, September 1996 (1996-09-01), pages 862 - 869, XP002039329 *

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6956103B2 (en) 1994-04-28 2005-10-18 The University Of Iowa Research Foundation Glaucoma therapeutics and diagnostics
US6171788B1 (en) 1997-01-28 2001-01-09 The Regents Of The University Of California Methods for the diagnosis, prognosis and treatment of glaucoma and related disorders
US6475724B1 (en) 1997-01-28 2002-11-05 The Regents Of The University Of California Nucleic acids, kits, and methods for the diagnosis, prognosis and treatment of glaucoma and related disorders
US7138511B1 (en) 1997-01-28 2006-11-21 The Regents Of The University Of California Nucleic acids, kits and methods for the diagnosis, prognosis and treatment of glaucoma and related disorders
US6403307B1 (en) 1997-03-21 2002-06-11 University Of Iowa Research Foundation Glaucoma therapeutics and diagnostics
WO1999051779A2 (fr) * 1998-04-07 1999-10-14 The University Of Iowa Research Foundation Traitement et diagnostic du glaucome
WO1999051779A3 (fr) * 1998-04-07 1999-12-29 Univ Iowa Res Found Traitement et diagnostic du glaucome
WO2000042220A1 (fr) * 1999-01-11 2000-07-20 The Regents Of The University Of California Acides nucleiques, kits, et methodes de diagnostic, de pronostic, et de traitement du glaucome et des troubles associes
AU775183B2 (en) * 1999-01-11 2004-07-22 Regents Of The University Of California, The Nucleic acids, kits, and methods for the diagnosis, prognosis and treatment of glaucoma and related disorders
WO2001088120A1 (fr) * 2000-05-17 2001-11-22 Tsubota Ltd. Gene associe au glaucome a angle ouvert, y compris le glaucome a tension oculaire normale
WO2020118293A3 (fr) * 2018-12-07 2020-07-23 Georgia Tech Research Corporation Anticorps qui se lient à la myociline pliée de manière native

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US6171788B1 (en) 2001-01-09
ATE375389T1 (de) 2007-10-15
NO993653L (no) 1999-09-28
AU742405B2 (en) 2002-01-03
EP1012271B1 (fr) 2007-10-10
DE69838553T2 (de) 2008-07-03
CA2278782A1 (fr) 1998-07-30
NO993653D0 (no) 1999-07-27
DE69838553D1 (de) 2007-11-22
AU5820498A (en) 1998-08-18
JP2001509669A (ja) 2001-07-24
NZ336860A (en) 2001-06-29
EP1012271A1 (fr) 2000-06-28
CA2278782C (fr) 2004-05-25

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